Midbrain <i>Tet1</i> dosage defines inter-individual binge-eating susceptibility

Binge-eating disorder (BED) is the most common eating disorder worldwide and carries life-altering comorbidities. While genetic and environmental risk factors have been identified, the mechanisms that determine inter-individual susceptibility to BED remain largely unknown. Here, we demonstrate that developmental dosage of the DNA hydroxymethylase <i>Tet1</i> defines stable inter-individual differences in binge-eating susceptibility. In mice, midbrain dopaminergic neurons of the ventral tegmental area (VTA ^DA ) are essential for the induction of addictive binge-eating behavior, express high levels of Tet1, and undergo rapid and widespread DNA hydroxymethylation remodeling upon experimental binge eating. Strikingly, <i>Tet1</i> haplo-insufficiency creates pronounced inter-individual variation in binge-eating susceptibility even among genetically identical mice, which we trace to reduced connectivity between the prelimbic medial prefrontal cortex (mPFC ^PL ) and the VTA. Chemogenetic inhibition of mPFC ^PL →VTA projections reduces binge-eating susceptibility, whereas EGR1-guided re-activation of TET1 in VTA dopaminergic neurons restores susceptibility, supporting a causal role for this axis. Importantly, <i>TET1</i> promoter methylation in patients associates with binge-eating behavior and reward-circuit function, suggesting conservation of this regulatory network in humans. Collectively, these findings identify <i>Tet1</i> dosage as a novel regulator of binge-eating susceptibility and provide a mechanistic basis for how inter-individual differences in behavior are established.